The primary goal of this transformative and translational research project is to develop revolutionary nanoparticle contrast agents and spectroscopic instrumentation in the near infrared for intraoperative cancer detection and image-guided surgery. The proposed technologies are broadly applicable to many types of solid tumors, but concerted efforts will be directed toward lung cancer, one of the most aggressive human malignancies and a worldwide health problem for both men and women. The overall rationale is that surgery cures approximately half of all cancer patients, while chemotherapy and radiation therapy cure only 5%. The single most important predictor of patient survival for almost all cancers is a complete surgical resection of the primary tumor, draining lymph nodes, and metastatic lesions. At the present, however, over 40% of patients that undergo surgery leave the operating room without a complete resection due to missed lesions. Thus there are urgent unmet needs and major opportunities to develop new and innovative technologies that can help the surgeon to delineate tumor margins, to identify micrometastases and draining lymph nodes, and to determine if the tumor has been completely removed. To accomplish this goal for lung cancer, we have assembled a collaborative team of 8 senior faculty investigators at three academic institutions (Emory University, Georgia Tech, and the University of Pennsylvania) with synergistic expertise in nanotechnology, instrumentation, software engineering, radiology, pathology, lung/thoracic surgery, and medical oncology. The proposed work will optimize two distinct types of near-infrared contrast agents and will further translate a handheld spectroscopic device and a wide-field multichannel imaging system for first-in-human applications. The first type of contrast agents is based on an FDA-approved dye (indocyanine green or ICG) and its albumin complexes, and will be used for device optimization and accelerated clinical feasibility studies. The second type of contrast agents is based on pegylated colloidal gold and surface-enhanced Raman scattering (SERS), a class of plasmonic nanocrystals that are able to enhance the Raman scattering efficiencies by 14-15 orders of magnitude, allowing spectroscopic detection and identification of single molecules and single nanoparticles at room temperature. For both types of contrast agents, we will use large animals (canines) with naturally occurring lung tumors (most relevant to the human disease) for tumor margin delineation as well as for image- guided resection of satellite lesions, micrometastases, and metastatic lymph nodes. In addition, we will conduct a Phase I/II clinical trial and examine if there is a benefit to standard-of-care approaches by enrolling approximately 30 human patients with non-small cell lung carcinoma (NSCLC).